Altered Global Gene Expression in First Trimester Placentas of Women Destined to Develop Preeclampsia

Abstract

Background Preeclampsia is a pregnancy-specific disorder that remains a leading cause of maternal, fetal and neonatal morbidity and mortality, and is associated with risk for future cardiovascular disease. There are no reliable predictors, specific preventative measures or treatments other than delivery. A widely-held view is that the antecedents of preeclampsia lie with impaired placentation in early pregnancy. Accordingly, we hypothesized dysregulation of global gene expression in first trimester placentas of women who later manifested preeclampsia. Methods Surplus chorionic villus sampling (CVS) tissues were collected at 10–12 weeks gestation in 160 patients with singleton fetuses. Four patients developed preeclampsia, and their banked CVS specimens were matched to 8 control samples from patients with unaffected pregnancies. Affymetrix HG-U133 Plus 2.0 GeneChips were utilized for microarray analysis. Naïve Bayes prediction modeling and pathway analysis were conducted. qRT-PCR examined three of the dysregulated genes. Results Thirty-six differentially expressed genes were identified in the preeclampsia placentas. qRT-PCR verified the microarray analysis. Thirty-one genes were down-regulated. Many were related to inflammation/immunoregulation and cell motility. Decidual gene dysregulation was prominent. No evidence was found for alterations in hypoxia and oxidative stress regulated genes. Conclusions To our knowledge, this is the first study to show dysregulation of gene expression in the early placentas of women ~6 months before developing preeclampsia, thereby reinforcing a placental origin of the disorder. We hypothesize that placentation in preeclampsia is compromised in the first trimester by maternal and fetal immune dysregulation, abnormal decidualization, or both, thereby impairing trophoblast invasion. Several of the genes provide potential targets for the development of clinical biomarkers in maternal blood during the first trimester. Supplementary materials are available for this article via the publisher’s online edition.

Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations

“…41 It was reported as up-regulated in chorionic villus samples of women who went on to experience preeclampsia. 42 In accord with this result, elevated FSTL-3 at mid gestation was associated with an increased risk of the development of this pregnancy complication. 43 The upregulated group also included MTSS1L (or ABBA), which is a signal transduction molecule that links the plasma membrane to the actin cytoskeleton.…”

HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia

“…A limitation of this experiment is that the analysis was performed on placental specimens obtained at delivery, whereas the hypoxia-HIF-KDM3A-MMP12 regulatory circuit we described is associated with an early pregnancy event. Nevertheless, the idea that MMP12 is dysregulated in preeclampsia is not unique to the present research; it is also supported by transcriptome profiling of chorionic villus samples (10-12 wk of gestation) from pregnancies destined to develop preeclampsia (47).…”

The content of matrix metalloproteinase-12 in pregnancy complicated by preeclampsia

“…Как извест но, «недостаточная» перестройка стенок спиралевидных маточ-ных артерий приводит к изменению строения и функционирования плаценты на протяжении всей беременности [3]. S.A. Founds et al выявили снижение экспрессии мРНК ММП-12 в клетках плацентарной ткани в I триместре у женщин с преэклампсией [21]. Исследований, посвя-щенных определению концентрации ММП-12 в сыворотке крови на протяжении беременно-сти, в доступной литературе найдено не было.…”